Malignant brain tumors, such as glioblastoma, remain the most difficult neoplasms to treat despite intensive multimodal treatment including surgical resection, radiation therapy, and systemic chemotherapy. Systemic chemotherapy requires high doses of many anticancer drugs because of poor penetration of the blood-brain barrier (see Groothuis D R. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro Oncol. 2000; 2(1):45-59. Also, see Huynh G H, Deen D F, Szoka F C Jr. Barriers to carrier mediated drug and gene delivery to brain tumors. J Control Release. 2006; 110(2):236-259). Consequently, systemic side effects are the limiting factor in chemotherapeutic protocols for patients with brain tumor, and emphasize the need for efficient, specific methods of delivery in the treatment of human glioblastoma.
Convection-enhanced delivery (CED) is a delivery system that circumvents the blood-brain barrier by delivering agents directly into the tumor and surrounding parenchyma based on continuous positive-pressure infusion (see Bobo R H, Laske D W, Akbasak A, Morrison P F, Dedrick R L, Oldfield E H. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA. 1994; 91(6):2076-2080). CED can achieve large volumes of distribution, as it is driven not only by the diffusive spread derived from concentration gradients, but also by continuous positive-pressure infusion (see Chen M Y, Lonser R R, Morrison P F, Governale L S, Oldfield E H. Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg. 1999; 90(2):315-320). Importantly, CED provides direct access to the tumor bed, thus resulting in high local concentrations of drug with minimal systemic absorption (see Yun J, Rothrock R J, Canoll P, Bruce J N. Convection-enhanced delivery for targeted delivery of antiglioma agents: the translational experience. J Drug Deliv. 2013; 2013:107573). Currently, CED has been clinically tested in the treatment of neurodegenerative diseases, such as Parkinson's disease (see Eberling J L, Jagust W J, Christine C W, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology. 2008; 70(21):1980-1983. Also, see Gill S S, Patel N K, Hotton G R, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003; 9(5):589-595), and neuro-oncology (see Kunwar S. Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. Acta Neurochir Suppl. 2003; 88:105-111. Also, see Mardor Y, Roth Y, Lidar Z, et al. Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging. Cancer Res. 2001; 61(13):4971-4973).